Journal
EXPERIMENTAL BIOLOGY AND MEDICINE
Volume 240, Issue 12, Pages 1580-1589Publisher
SAGE PUBLICATIONS LTD
DOI: 10.1177/1535370215579018
Keywords
Pulmonary hypertension; microRNAs; endothelial cell proliferation; anti-miRs; BMPR2
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Funding
- Actelion Pharmaceutical Ltd, Switzerland
- Actelion and Bayer AG, Germany
- Swiss National Science Foundation (SNF) [31003A_144212]
- Zurich Lung Foundation
- EMDO Foundation
- Theodor and Ida Herzog-Egli Foundation
- Swiss National Science Foundation (SNF) [31003A_144212] Funding Source: Swiss National Science Foundation (SNF)
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Vascular remodeling due to excessive proliferation of endothelial and smooth muscle cells is a hallmark feature of pulmonary hypertension. microRNAs (miRNAs) are a class of small, non-coding RNA fragments that have recently been associated with remodeling of pulmonary arteries, in particular by silencing the bone morphogenetic protein receptor type II (BMPR2). Here we identified a novel pathway involving the concerted action of miR-125a, BMPR2 and cyclin-dependent kinase inhibitors (CDKN) that controls a proliferative phenotype of endothelial cells. An in silico approach predicted miR-125a to target BMPR2. Functional inhibition of miR-125a resulted in increased proliferation of these cells, an effect that was found accompanied by upregulation of BMPR2 and reduced expression of the tumor suppressors CDKN1A (p21) and CDKN2A (p16). These data were confirmed in experimental pulmonary hypertension in vivo. Levels of miR-125a were elevated in lung tissue of hypoxic animals that develop pulmonary hypertension. In contrast, circulating levels of miR-125a were found to be lower in mice with pulmonary hypertension as compared to control mice. Similar findings were observed in a small cohort of patients with precapillary pulmonary hypertension. These translational data emphasize the pathogenetic role of miR-125a in pulmonary vascular remodeling.
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